Clinical Considerations in the Management of Individuals at Risk for Hereditary Breast and Ovarian Cancer

Mark E. Robson, MD

Disclosures

Cancer Control. 2002;9(6) 

In This Article

Prevention Options for Women With BRCA Mutations

As the screening programs recommended to women at risk for hereditary breast and ovarian cancer are of uncertain effectiveness, a number of women with BRCA mutations consider undergoing surgical procedures in an attempt to reduce their risk. Bilateral risk-reducing mastectomy has been reported to be at least 90% effective in reducing breast cancer incidence and mortality in women with a family history of breast cancer, and this approach appears to be effective in women with BRCA mutations.[61,62] The procedure is not completely protective because of the risk of developing cancer in microscopic rests of breast tissue that are not removed at the time of surgery. Despite the evident effectiveness of the procedure, the uptake of risk-reducing mastectomy has been modest, presumably because of the significant physical and psychological morbidity attendant on the procedure.

Risk-reducing salpingo-oophorectomy is more frequently employed, particularly in women who have completed childbearing and are nearing menopause. When performed laparoscopically, the acute morbidity of the procedure is modest, although the quality-of-life consequences and long-term health risks of premature estrogen deprivation have not been defined. BRCA mutations are associated with an increased risk of fallopian tube carcinoma, and complete removal of both tubes and ovaries is indicated. However, there is no clear evidence of an increased risk of uterine cancer in BRCA heterozygotes, and thus hysterectomy is not necessary in the absence of another gynecologic indication. Two studies have now demonstrated a significant reduction in ovarian cancer risk after risk-reducing oophorectomy.[63,64] These studies and others have also noted a significant reduction in breast cancer risk in women undergoing oophorectomy, which constitutes a substantial collateral benefit to the procedure.[65]

A number of decision analyses have been performed in an attempt to compare the relative benefits of surveillance and preventive surgery in women with BRCA mutations.[66,67] While these analyses are uniformly supportive of surgical approaches, they can easily be misinterpreted and should not be used for counseling of individuals considering surgery. These studies project life-expectancy gains for women undergoing specific interventions, using a series of assumptions that may not be robust, depending on the amount of data underpinning them. As these studies report anticipated benefits as average gains distributed across a population, they may markedly underestimate (or overestimate) the benefit that will be experienced by a particular individual.

Nonsurgical options for the prevention of hereditary breast cancer are currently limited. Tamoxifen was shown in a case-control study to reduce the risk of new contralateral breast primaries in women taking the drug for their initial breast cancer diagnosis.[68] However, a subset analysis of the prospective Breast Cancer Prevention Trial, carried out in unaffected women at risk, failed to demonstrate a significant risk reduction in BRCA mutation carriers.[69] The lack of statistical significance may have resulted from the limited power of the small subset analysis. Alternatively, selective estrogen receptor modulators such as tamoxifen or raloxifene do not appear to reduce the incidence of estrogen receptor-negative tumors, which BRCA1 heterozygotes, in particular, are at risk to develop. Until further data become available, the use of tamoxifen and similar drugs for the prevention of BRCA-associated breast cancer should be considered investigational. Tamoxifen is still appropriate and clearly indicated as adjuvant therapy for women with hormone receptor-positive tumors, whether or not a germline BRCA mutation is present.

Oral contraceptives may be considered for the reduction of ovarian cancer risk in BRCA heterozygotes,[70] although not all studies have demonstrated effectiveness.[71] It is important to note that the impact of oral contraceptives on BRCA-associated breast cancer risk has not yet been defined, and young women with documented mutations should probably not take the drugs indefinitely as the incremental benefit in ovarian cancer risk reduction is likely to be modest after approximately 5 years of exposure.

Finally, although not a nonsurgical option, it is worth noting that one study has demonstrated a reduction in ovarian cancer risk among BRCA heterozygotes in women who have undergone tubal ligation.[72]

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